Shared Genetics and Modifiable Factors in Myopia and Retinal–Optic Nerve Disease

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Myopia has long been associated with an increased risk of several vision-threatening retinal and optic nerve diseases, but whether these associations reflect shared biology or simply the structural consequence of axial elongation remains unclear. Gao and colleagues sought to characterize the epidemiologic, genetic and environmental relationships between myopia and five common retinal-optic nerve diseases (RONDs): retinal detachment (RD), primary open-angle glaucoma (POAG), primary angle-closure glaucoma (PACG), age-related macular degeneration (AMD) and diabetic retinopathy (DR).

Study Design

• Population-based study using 81,491 participants from the U.K. Biobank
• 27,355 participants met the definition of myopia (≤ –0.50D spherical equivalent)
• Myopia categorized as:
  • Mild (-0.50D to -3.00D)
  • Moderate (-3.00D to -6.00D)
  • High (≤ -6.00D)
• Evaluated both prevalent and incident RONDs
• Combined epidemiologic analyses with:
  • Genome-wide association studies (GWAS)
  • Genetic correlation analyses
  • Pleiotropy and colocalization analyses
  • Gene-environment interaction analyses
  • Mendelian randomization (MR)

Key Findings

• Retinal detachment (RD)
  • Strongest association observed among the diseases studied
  • Risk increased with myopia severity:
    • Mild: hazard ratio (HR) 1.71
    • Moderate: HR 3.16
    • High: HR 4.88
• Primary open-angle glaucoma (POAG)
  • Risk increased with increasing myopia severity
  • Moderate myopia: HR 1.48
  • High myopia: HR 2.01
• Primary angle-closure glaucoma (PACG)
  • Myopia was associated with significantly lower risk
  • Mild myopia: HR 0.27
  • Moderate myopia: HR 0.10
• Age-related macular degeneration (AMD)
  • Demonstrated a U-shaped relationship with refractive error
  • Increased risk observed in both high myopia and hyperopia
• Diabetic retinopathy (DR)
  • Point estimates suggested lower risk among myopic individuals
  • Associations were not consistently statistically significant
• Genetic analyses
  • Identified 66 pleiotropic genomic loci and 115 candidate genes
  • Significant shared genetic architecture was observed between myopia and RD, POAG, and PACG
  • Enriched biologic pathways included:
    • Immune and inflammatory signaling
    • Complement activation
    • Extracellular matrix remodeling
    • Receptor-mediated signaling
    • Retinal development

Beyond the epidemiologic associations, the investigators also evaluated modifiable factors associated with RONDs among individuals with myopia. Several modifiable factors including diabetes, hypertension, smoking, physical activity, diet, sleep characteristics, mental health measures and aspirin use were associated with varying levels of risk across the retinal-optic nerve diseases studied. Gene-environment analyses further identified significant interactions involving sleep-related factors, physical activity and mental health measures, suggesting these exposures may modify genetic susceptibility. However, the authors note that these findings should be considered exploratory until validated in additional populations.

Limitations

• Participants were primarily middle-aged adults of European ancestry, which may limit generalizability to more diverse populations and pediatric patients.
• Myopia was classified using refractive error rather than axial length, which may not fully capture the structural changes associated with progressive myopia.
• Gene-environment interaction findings were exploratory and required external validation.
• Although MR supported associations for RD and PACG, findings for POAG and DR were less conclusive because of pleiotropy and heterogeneity.

Clinical Relevance

This study confirms previously reported associations between myopia and retinal detachment, primary open-angle glaucoma, and primary angle-closure glaucoma while providing evidence of shared genetic architecture across these conditions. The identification of common genomic loci and biologic pathways offers additional insight into the relationship between myopia and retinal-optic nerve diseases and provides a foundation for future mechanistic and prevention-focused research.

My Take

The most notable finding was the identification of shared genetic architecture between myopia and several retinal-optic nerve diseases. Although these results are unlikely to change clinical practice today, they provide a foundation for future research into disease mechanisms and prevention.

Abstract

Shared Genetic Architecture and Multidimensional Modifiable Correlates between Myopia and Retinal–Optic Nerve Diseases

Gao Y, Xu J, Yu J, Zhang Y, Chen H, Ho M, Kam KW, Young AL, Pang CP, Tham CC, Yam JC, Chen LJ